Oxygen-Amplified Carrier-Free Nanomedicine Integrating Ferroptosis/Photodynamic Therapy and COX-2/PGE2 Blockade for Robust Antitumor Immunity Against Glioma.

The therapeutic efficacy of glioma immunotherapy is severely hampered by immunosuppression in the tumor microenvironment. Here, we develop an oxygen‑amplified carrier‑free nanomedicine (IHC NPs) through hydrophobic self‑assembly of IR-820, hemin, and celecoxib. IHC NPs exhibit excellent stability, biological safety, and preferential tumor accumulation. In the subcutaneous glioma model, the combination of IHC NPs and αPD-L1 significantly inhibited subcutaneous tumor growth and effectively prevented distant tumor metastasis. Mechanistically, hemin catalyzes endogenous H2O2 to generate oxygen, thereby alleviating tumor hypoxia. This oxygen boost potentiates IR-820‑mediated photodynamic therapy and hemin-based ferroptosis, enhancing direct tumor cell killing. Concurrently, celecoxib blocks the COX‑2/PGE2 pathway, reversing immunosuppression within the tumor microenvironment. Through the synergistic strategy combining oxygen-sensitized photodynamic therapy, ferroptosis, COX-2/PGE2 suppression, and PD-1/PD-L1 blockade, this therapeutic regimen effectively induces tumor immunogenic cell death, promotes dendritic cell maturation, enhances intratumoral infiltration of cytotoxic T lymphocytes, reduces the abundance of regulatory T cells, and triggers the generation of effector memory T cells, thereby potently activating the host immune system. Collectively, our work provides a promising oxygen‑amplified carrier‑free nanomedicine for robust glioma immunotherapy.